title: Cytoplasmic localization of wild-type survivin is associated with constitutive activation of the PI3K/Akt signaling pathway and represents a favorable prognostic factor in patients with acute myeloid leukemia.
abstract: Survivin is over-expressed in most hematologic malignancies but the prognostic significance of the subcompartmental distribution of wild-type or splicing variants in acute myeloid leukemia has not been addressed yet. Using western blotting, we assessed the expression of wild-type survivin and survivin splice variants 2B and Delta-Ex3 in nuclear and cytoplasmic protein extracts in samples taken from 105 patients at the time of their diagnosis of acute myeloid leukemia. Given that survivin is a downstream effector of the PI3K/Akt signaling pathway, survivin expression was also correlated with pSer473-Akt. Wild-type survivin and the 2B splice variant were positive in 76.3% and 78.0% of samples in the nucleus, cytoplasm or both, whereas the Delta-Ex3 isoform was only positive in the nucleus in 37.7% of samples. Cytoplasmic localization of wild-type survivin was significantly associated with the presence of high levels of pSer473-Akt (P<0.001). Inhibition of the PI3K/Akt pathway with wortmannin and Ly294002 caused a significant reduction in the expression of cytoplasmic wild-type survivin. The presence of cytoplasmic wild-type survivin and pSer473-Akt was associated with a lower fraction of quiescent leukemia stem cells (P=0.02). The presence of cytoplasmic wild-type survivin and pSer473-Akt were favorable independent prognostic factors. Moreover, the activation of the PI3K/Akt pathway with expression of cytoplasmic wild-type survivin identified a subgroup of acute myeloid leukemia patients with an excellent outcome (overall survival rate of 60.0±21.9% and relapse-free survival of 63.0±13.5%). Our findings suggest that cytoplasmic wild-type survivin is a critical downstream effector of the PI3K/Akt pathway leading to more chemosensitive cells and a more favorable outcome in acute myeloid leukemia.
authors.affiliation: joaquin.sanchez@cheerful.com.
authors.forename: Juana
authors.initials: J
authors.lastname: Serrano-López
authors.forename: Josefina
authors.initials: J
authors.lastname: Serrano
authors.forename: Vianihuini
authors.initials: V
authors.lastname: Figueroa
authors.forename: Antonio
authors.initials: A
authors.lastname: Torres-Gomez
authors.forename: Salvador
authors.initials: S
authors.lastname: Tabares
authors.forename: Javier
authors.initials: J
authors.lastname: Casaño
authors.forename: Noemi
authors.initials: N
authors.lastname: Fernandez-Escalada
authors.forename: Joaquín
authors.initials: J
authors.lastname: Sánchez-Garcia
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D018922:HL-60 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000032:analysis / Q000096:biosynthesis*; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015996:Survival Rate / Q000639:trends; D000077022:Survivin; D055815:Young Adult
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt